Alzheimer's disease (AD) affects more than 12 million patients worldwide, accounting for most dementia diagnosed after the age of 60. The disease is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bedridden, incontinent and dependent on custodial care; death occurs, on average, nine years after diagnosis (Davis et al., in Pharmacological Management of Neurological and Psychiatric Disorders, pp. 267-316, 1998). In addition to its direct effects on patients, advanced AD puts a tremendous burden on family caregivers and causes high nursing home costs for society. Age is the major risk factor for AD, and a health care crisis is likely in countries with aging populations if treatments that protect against the disease or delay or stop its progression cannot be introduced within the next decade. The current standard of care for mild to moderate AD includes treatment with acetylcholine-esterase inhibitors to improve cognitive function (Doody, R., Alzheimer Dis. Assoc. Disord., 13:S20-S26, 1999). These drugs are safe, but of limited benefit to most patients. Other drugs are used to manage mood disorder, agitation and psychosis, but no treatment with a strong disease modifying effect is currently available.
Much of AD research has been focused on the amyloid cascade which predicts that Aβ, a proteolytic derivative of the large transmembrane protein APP, has an early and critical role in all cases of AD. Aβ forms aggregates that are thought to initiate a pathogenic cascade ultimately leading to neuronal loss and dementia (Hardy et al., Trends Pharmacol., 23:383-288, 1991). The amyloid cascade hypothesis was originally formulated based on pathological evidence. Two pathological hallmarks of AD are extracellular amyloid plaques, predominantly of Aβ42, and intraneuronal tangles of an aggregated form of the neuronal protein tau. Amyloid plaques are relatively specific for AD, whereas tangles are also found in other disorders (Joachim et al., Alzheimer Dis. Assoc. Disord., 6:7-34, 1992). Genetic analysis of the rare, familial autosomal-dominant AD with early onset has led to the identification of disease-causing mutations in three genes: amylold precursor protein (APP), presenilin1 (PS1) and presenilin2 (PS2). The only common effect of all these mutations is an increased production of Aβ42, which is therefore assumed to cause disease pathogenesis (Younkin, S., J. Physiol., 92:289-292, 1998; Selkoe, D., Nature, 399:A23-A31, 1999). In contrast, the cause for the more common, sporadic, late-onset AD remains unknown. Based on the similarities in pathology (in particular, the massive Aβ42 accumulation) and clinical presentation of familial and sporadic AD, it is widely accepted that Aβ42 is critical in both.
The amyloid cascade is initiated when Aβ42 is proteolytically generated from APP by the sequential action of two proteases, β-secretase and γ-secretase. Because Aβ42 generation is the first step in the cascade, shutting down or reducing its production is desirable. Beginning in 1992, some companies initiated cell-based screens for inhibitors that are reported to have provided potent γ-, but not β-secretase inhibitors. In 2001, Bristol-Myers-Squibb announced that the first of these γ-secretase inhibitor compounds had moved into phase 2 clinical trials (P. Molinoff et al., Symposium on Molecular Mechanisms and Therapeutic Strategies for Neurodegenerative Diseases, Shanghai, 2001). The results of trials have not yet been released. The status of the cell-based γ-secretase inhibitor programs at most other companies has not been disclosed. β-secretase has been identified and its structure has been solved (Citron, M., Nature, 5:1055-1057, 2002). Peptidic β-secretase inhibitors have been featured in several publications (Sinha et al., Nature, 402:537-540, 1999).
There are numerous targets for therapeutic intervention of the amyloid cascade downstream of Aβ generation. On theoretical grounds, anti-aggregation approaches are very attractive-whereas Aβ generation is a physiological event, aggregation of monomeric Aβ into oligomers and fibrils with β-sheet structure is considered pathogenic. Small-molecule inhibitors of the interaction between Aβ and glycosaminoglycans, which is proposed to be involved in the formation of amyloid deposits in Alzheimer's disease, have been reported, and in vivo efficacy of these compounds has been demonstrated in amyloid mice. (F. Gervais et at., 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 2002). Short peptidic Aβ derivatives, have also been reported to show in vivo efficacy upon intraperitoneal injection in the amyloid mouse (C. Soto et al., 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, 2002). Chelating zinc (reported to be critical for Aβ aggregation) with the antibiotic clioquinol has been reported to lower amyloid burden in vivo (Cherny et al., Neuron, 30:665-66, 2001; Bush et al., PNAS, 98:8850-8855, 2001).
Another approach to AD treatment involves immunotherapy. Amyloid mice vaccinated with fibrillar Aβ42 were reported to have reduced plaque pathology (Schenk et al., Nature, 400:173-177, 1999). The vaccination effect could be mimicked by peripheral administration of anti-Aβ antibodies that bind plaques. It was proposed that small quantities of peripherally administered anti-Aβ antibodies cross into the brain, where they label amyloid plaques and activate surrounding microglia to phagocytose and thus clear Aβ deposits. This mechanism was modeled in an ex vivo assay, in which cultured microglia clear Aβ deposits from sections of AD brains upon addition of anti-Aβ antibodies; this assay predicted in vivo efficacy in the mouse model (Bard et al., Nat. Med., 6:916-919, 2000). An alternative mechanism of action suggests that certain Aβ antibodies act primarily as a peripheral sink, essentially pulling soluble Aβ peptide from the brain into the periphery, where it is cleared (DeMattos et al., PNAS, 98:8850-8855, 2001). Regardless of the exact mechanism, it seems that antibodies to Aβ are efficacious at reducing plaque burden in transgenic mouse models. Based on these findings, Elan Corporation, in collaboration with Wyeth, moved into clinical trials with an Aβ vaccination approach. The trials were stopped in phase 2A when six percent of patients developed meningo-encephalitis (Steinberg, D., The Scientist, 16:22-23, 2002).
Of interest are U.S. Pat. No. 6,787,637 and U.S. Application Publication Nos. 2004/0171815 and 2004/0171816, which disclose the use of anti-amyloid antibodies and humanized anti-amyloid antibodies, in the treatment of Alzheimer's disease. The anti-amyloid antibodies disclosed in these publications were introduced into mice to evaluate their ability to reduce Aβ levels and were also tested for their ability to induce phagocytosis.
Retrospective epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) (drugs such as aspirin, which, among other actions, inhibit the cyclo-oxygenase cox-2) provide some degree of protection from AD. It is proposed that at least part of the AD phenotype is due to chronic brain inflammation (McGeer et al., Neurobiol Aging, 22:799-809, 2001). A small trial of indomethacin hinted at an improvement, but large placebo-controlled trials of specific COX2 inhibitors in AD have not been successful, implying that inhibition of this target does not change the disease course (Citron, M., Nat. Rev. Neurosci., 5:677-685, 2004). Epidemiological studies also suggest that treatment with statins, inhibitors of the cholesterol-synthesizing enzyme HMG-CoA-reductase, also protects from Alzheimer's disease (Wolozin et al., Arch. Neurol., 57:1439-1443, 2000; Jick et al., Lancet, 356:1627-1631, 2000). The mechanism may be through direct effects on Aβ42 production (Fassbender et al., PNAS, 98:5856-5861, 2000), although microvascular and endothelial effects of the statins and other indirect mechanisms cannot be excluded (Golde et al., Drug Discov. Today, 6:1049-1055, 2001).
There continues to exist the need for new therapies and reagents for the treatment of Alzheimer's disease, in particular, therapies and reagents capable of effecting a therapeutic benefit without significant adverse effects.